Comparison of the Effect of Phenobarbital versus Sodium Valproate in Management of Children with Status Epilepticus.

Objectives
Acute prolonged seizure is the most common neurological emergency in children. This research was conducted to compare the effect of intravenous phenobarbital and Sodium valproate in control of seizure in children with status epilepticus, referred to emergency ward from Mar to Nov 2013.


Materials & Methods
In this randomized clinical trial, registered with the code number IRCT2015051722300N1, 80 children aged 6 months to 10 years with prolonged seizure and with no response to one dose of diazepam (0.2 mg/kg) administered through IV injection during the five min were selected. Children were randomly divided into two groups, intervention, and control through permutation blocks. In intervention group, intravenous Sodium valproate (20 mg/kg) and in control group, intravenous phenobarbital (20 mg/kg) were prescribed. Data such as age, gender, history of previous seizure, seizure type, and recovery time after receiving drug was recorded in the form. Data analysis was done through descriptive statistics, Chi-square and Independent t- test.


Results
Two groups were the same in terms of age and gender and had no statistically significant difference, but they were different in terms of seizure type. In valproate group, 18 patients (45%) and in phenobarbital group, 32 patients (80%) had positive response to the treatment and the chi-square test showed the significant difference.


Conclusion
With regards to this point that in phenobarbital group, patients had more rapid response to drug in comparison with patients in Sodium valproate group, phenobarbital is a suitable and effective drug for controlling of seizure in children.


Introduction
Seizure is defined as paroxysmal and transient changes in motor, behavioral or autonomic activity followed by disturbance in brain electrical activity (1). Seizure is one of the causes of hospitalization in children and acute prolonged seizure is the most common emergency in Pediatric Neurology Emergency (2). In a six-month random sampling of all of the hospitalized patients in Pediatric Emergency Ward in Amin and Al-Zahra hospitals in Isfahan, central Iran, 60% of hospitalized children had seizure (3). Prolonged seizure is associated with high mortality, especially when it leads to complications such as acidemia, hypoglycemia or hypotension. Timely and effective treatment can improve the prognosis of disease and decrease some complications such as metabolic acidosis and aspiration pneumonia (4).
If seizures last longer than 5 min and the patient does not wake up between them, it is a medical emergency. Status epilepticus is a medical emergency that should be anticipated in any patient who presents with an acute seizure. It is defined as continuous seizure activity lasting more than 30 min or two or more seizures without full recovery of consciousness between any of them lasting for more than 5 minutes. In the past, the cutoff time was 30 min, but this has been reduced to emphasize the risks involved with the longer durations. Moreover, febrile status epilepticus is a febrile seizure lasting longer than 30 min (1).
Since the prevalence of seizure disorders in children is higher than in adults, the using of anti-seizure drugs is high in this age group (5). An ideal antiseizure drug should have suitable performance, reaches the brain quickly and have minimal side effects. Routinely, benzodiazepines are the firstline treatment of seizures in the emergency (6).
When the benzodiazepines are not successful in treating seizure, the long-acting anti-seizure drugs should be used (7). In developing countries, phenobarbital and phenytoin are the most common second-line anti-epileptic drugs (8). Phenobarbital was the first antiepileptic drug introduced in 1912.
Nowadays, phenobarbital is commonly used for seizure disorders. Although this drug is less effective than phenytoin or carbamazepine, but it is used for treatment of generalized tonic-clonic and partial epilepsies in all age groups (9). Good efficacy, low toxicity and low cost of the drug have suggested it as an important drug for such applications.
There is evidence that phenobarbital has the most powerful effect in damaging to the behavioral and cognitive activities. The administration of phenobarbital during growth may lead to cognitive impairments such as damage to memory and learning abilities.
Respiratory depression and hypotension are the side effects of rapid phenobarbital infusion, but the most important long-term side effect that limits its use is the impact on children's behavior and learning (10). Sodium valproate as a broadspectrum anticonvulsant is one of the classic anticonvulsants and is available in our country.
This drug is effective in all types of seizures such as absence, tonic-clonic and myoclonic. Besides, it is effective on some kinds of partial epilepsy.
The effect of sodium valproate and phenytoin in patients with status epilepticus were compared and the sodium valproate was more effective than phenytoin (11). Moreover, in a study to determine The efficacy of sodium valproate and phenytoin as the first-line treatment in status epilepticus were compared and showed that there was no significant difference between two groups in terms of seizure control, length of stay in hospital, mortality and serious cardiovascular complications (13).
Considering the importance of these cases,

Materials & Methods
This randomized single-blind clinical trial study registered with the code number The frequency distribution of seizures type showed that in both groups, the most common seizure was status epilepticus. Besides, two groups were similar in terms of type of seizure at the beginning of the study and chi-square test did not show significant difference between the two groups (Table 1). In addition, the mean response time to drug in both groups was assessed according to type of seizure.
In phenobarbital group, response to drug in patients with SE lasted longer time than the patients with FC and this difference was significant (P=0.04).
Unlike, in Sodium valproate group, response to drug in patients with FC lasted longer time than the patients with SE, but this difference was not significant (Table 3).  Besides, comparison the mean and standard deviation of response time concerning the gender in both groups showed that this mean was more in female children than male children in intervention group were, but the t-test did not show significant difference. In control group, this time in female patients was more than the male patients and t-test showed no significant difference (Table 4). There was a significant direct relationship between the age and response time in all of the patients. In other words, with increasing the patient's age, the response time to drug was increasing that is similar to results that the children with higher mean age had more rapid positive response to drug in compared with younger children (17).
Generally, by comparing the results of various studies with current study, both sodium valproate and phenobarbital are effective drugs in second-line treatment in patients with seizures especially with regard to the type of seizure. The sodium valproate had more effectiveness, the type of seizure was status epilepticus, but the phenobarbital had been more effective, the type of seizure was generalized and partial. In our study, valproate sodium was more effective in patients with status epilepticus.
In conclusion, the phenobarbital in comparison with sodium valproate is a suitable and effective drug for controlling of seizure in children.